A Narrative Review of Novel Agents for Managing Heavily Treatment-Experienced People Living With HIV

Abstract

Objective: The objective of this review is to compare ibalizumab, fostemsavir, and lenacapavir, present the clinical trials evaluating each agent, and provide guidance on their use in highly-treatment experienced (HTE) population living with HIV (PWH). Data sources: A search of PubMed and clinicaltrials.gov was conducted using the search terms: ibalizumab, fostemsavir, and lenacapavir. Study selection and data extraction: English-language, clinical publications were included. Data synthesis: Ibalizumab, fostemsavir, and lenacapavir, are each first-in-class agents, that have major differences in mechanism of action, route and frequency of administration, pharmacokinetic parameters, including elimination half-life, potential for drug-drug interactions, safety profiles, and cost. Each has been shown, when combined with an optimized background regimen (OBR) with at least one other active agent, to achieve virologic suppression in HTE-PWH. Conclusion: In HTE-patients, adding ibalizumab, fostemsavir, and/or lenacapavir to at least one other active agent can lead to virologic suppression in this difficult to treat population. Monotherapy with any of these agents is not recommended and will lead to a high likelihood of drug resistance. Selection of which agent(s) to include with an OBR will depend on other patient factors including concomitant medications, acceptance of formulations (oral vs. subcutaneous vs. intravenous infusion), and potential access (both insurance-based and transportation). Adherence to all agents in the regimen is paramount to successful outcomes.

Introduction

Resistance to antiretroviral therapy (ART) remains a primary cause of virologic failure, especially in heavily treatment-experienced (HTE) people with HIV (PWH). Resistance-associated mutations (RAMs) impacting ART efficacy may be acquired or developed due to suboptimal ART exposure and limit the effectiveness of individual antiretroviral agents (ARV) or entire antiretroviral classes. HIV with reduced susceptibility to either multiple ARVs or classes is considered multi-drug resistant (MDR). Heavily treatment-experienced patients compose <1% of PWH but determining optimal drug therapy in this population is essential as the risk of virologic and clinical progression are increased leading to higher rates of emergency department visits, hospitalizations, and mortality. ¹ Heavily treatment-experienced patients who cannot achieve/maintain an undetectable viral load (VL) are also at risk of transmitting HIV, including transmitting resistant viruses. Finally, HTE patients are estimated to have 30% greater HIV-related predicted lifetime costs compared to non-HTE patients. ¹ While achieving and maintaining virologic suppression may not be possible in every case, ² optimization of ART is important as any decrease VL>0.5log₁₀ copies/mL correlates with clinical benefit and decreased transmission.^3,4

With limited alternatives, HTE patients often remain on suboptimal regimens. The introduction of novel antiretroviral agents for HTE-PWH began with the release of enfuvirtide (2003), the first entry inhibitor. Enfuvrtide was burdened with administrative issues (twice daily subcutaneous injection) and poor tolerability (injection site reactions and painful nodules). The mid-2000s brought the introduction of 2 new classes of ARTs—raltegravir, the first integrase strand transfer inhibitor (INSTI), and maraviroc (CCR5-antagonist)—and 2 new options in the protease inhibitor and non-nucleoside reverse transcription inhibitor class, ritonavir-boosted darunavir and etravirine. These ARVs, when used in combination with 1 or 2 other active or partially active agents to create an optimized background regimen (OBR), were often able to provide a relatively well-tolerated option for many HTE-PWH allowing the achievement of virologic suppression. Downsides to these ARVs were usually related to pill burden, gastrointestinal distress, and twice-daily administration. Over the next decade, few new options for HTE patients were introduced.

Starting in 2018, several first-in-class antiretroviral agents with novel mechanisms of action were approved for use in HTE-PWH. Two agents targeted viral attachment/entry—ibalizumab (Trogarza, 2018) and fostemsavir (Rukobia,2020)—and one agent inhibited capsid formation—lenacapavir (Sunlenca, 2023). Important differences among the 3 agents in administration, drug-drug interaction potential, and adverse effects are present and could impact use based on patient characteristics (See Table 1). This review compares these new agents, reviews the literature describing their use in HTE-PWH, and provides guidance on optimal use in this difficult-to-treat population.

Table 1.

Characteristics of Ibalizumab, Fostemsavir, and Lenacapavir.

	Ibalizumab 5	Fostemsavir 6	Lenacapavir 7
Indication	In combination with other antiretrovirals for treatment of HIV-1 in HTE adults failing current ART
Mechanism of action	CD4 directed postattachment inhibitor	Gp120-directed attachment inhibitor	Capsid inhibitor
Pharmacokinetics	T1/2: 3.1-3.3 days	T1/2: 11 hours Metabolism: prodrug converted to active moiety by esterases; a metabolite of CYP3A4and UGT Excretion: 51% unchanged in the urine	T1/2: 8-12 weeks (SQ), 10-12 days (PO) Metabolism: CYP3A4 and UGT1A1 Excretion: <1% unchanged in urine Bioavailability: 6%-10% (oral formulation)
Administration	Intravenous Infusion: 2000 mg loading dose over 30 minutes followed by 800 mg over 15 minutes every 2 weeks Must monitor for infusion-related adverse effects for 1 hour after 1st infusion and 15 minutes thereafter. Diluted in 250 mL of 0.9% NaCl Stable at room temperature for 4 hrs and refrigerated for 24 hrs	Oral administration (600 mg tablets) One tablet by mouth twice daily with or without food Tablet should not be chewed, crushed, or split	Oral lead in with subcutaneous maintenance
			Load Option 1 Day 1: 927 mg SQ (2 injections) and 2 × 300 mg PO Day 2: 600 mg PO	Load Option 2 Day 1: 2 × 300 mg PO Day 2: 2 × 300 mg PO Day 8: 1 × 300 mg PO Day 15: 927 mg SQ
			Maintenance 927 mg SQ every 26 weeks from the date of last injection (±2 weeks)
Missed doses	If missed by >3 days must re-administer loading dose	Take as soon as remembered, do not double dose	Restart from day 1 if more than 28 weeks have passed since last dose administration
Adverse effects (>3%)	Diarrhea, dizziness, nausea, rash	Nausea	Injection site reactions (include swelling, pain, erythema, nodule, induration, pruritus, extravasation, and mass) nausea
Drug interaction potential	No major drug interactions noted	CYP3A4, QT-prolongation agents	CYP3A4, P-gp, UGT1A1
Renal Impairment	No information provided No required adjustments expected	No dosage adjustment required for renal impairment No dosage adjustments required for hemodialysis	No dosage adjustment required with estimated CrCl ≥15 ml/min PK data are unknown in those with end-stage renal disease
Hepatic impairment	No required adjustments expected No formal studies or information provided per manufacturer	No dose adjustment required for mild, moderate, or severe hepatic impairment (Child-Pugh A-C)	No dose adjustment required in mild-moderate hepatic impairment (Child-Pugh Class A-B) PK data are unknown in those with Child-Pugh Class C
Pregnancy	Data are inadequate	Data are inadequate	Data are inadequate
Pediatric/geriatric	Data regarding usage is unavailable	No data in pediatric patients Limited data in geriatric patients, caution should be used	Limited data in pediatric and geriatric patients
Mutations of interest	N-linked glycosylation sites in V5 loop of HIV-1 gp120 8	S375N, M426L, M475, M4349,10	M66I, Q76I, K70R11 -13

Abbreviations: hr, hour; PO, oral administration; SQ, subcutaneous.

Methods

A search of the English-language literature in PubMed and clinicaltrials.gov was conducted using the following search terms: ibalizumab, fostemsavir, and lenacapavir. Additional references were obtained from the review of publications. The search identified literature describing the pharmacologic/pharmacokinetic characteristics of each agent and available controlled trials evaluating the efficacy, safety, and potential for resistance with the use of each agent in the HTE population.

Antiretroviral Reviews

Ibalizumab

Ibalizumab is a humanized monoclonal antibody that acts as an HIV entry inhibitor. By binding to domain 2 of the CD4 receptor, a conformational change in the CD4 receptor-gp120 complex (postattachment) occurs (Table 1). This change inhibits subsequent HIV fusion and entry into the cell. Ibalizumab, as part of an OBR, is administered as a biweekly infusion (2000 mg over 30 minutes for the first loading dose, then 800 mg over 15 minutes for subsequent maintenance doses). Minimal concerns for adverse effects or pharmacokinetic drug-drug interactions with ibalizumab have been reported.

Ibalizumab efficacy, pharmacokinetics (PK), and/or safety have been assessed in 3 clinical trials.^{14 -16} Initial Phase I and II trials of ibalizumab established effective antiviral activity with minimal toxicity.^14,15 An open-label, single-arm, phase III study evaluated the efficacy and safety of ibalizumab in patients with MDR HIV-1. ¹⁶ Eligibility criteria included adults with VL >1000 copies/mL on ART for at least 8 weeks before enrollment, who received ART for 6 months before screening, and had documented resistance to at least 1 drug in 3 classes of antiretrovirals. Optimized background regimens were required to contain at least one fully active agent (including investigational agents). After a control period consisting of a 6-week screening period and 1 week control period on current ART, patients received a 2000 mg intravenous ibalizumab loading dose while continuing their current ART. At day 7 postloading dose, patients were switched from current ART to an OBR. At day 14 postloading dose, ibalizumab 800 mg was infused and continued every 14 days through week 25 along with the OBR. The study enrolled 40 subjects (15% female, 33% black, median age of 53 years). Thirty-two (80%) subjects completed all ibalizumab doses. At baseline, the median VL was 4.6 (2.5-5.9) log₁₀ copies/mL and 67% of subjects had a CD4 <200 cells/mm³. Baseline resistance to ≥1 drug was seen in 93%, 68%, 90%, and 93% of the NRTIs, INSTIs, PIs, and NNRTIs classes, respectively. Specific components of patient’s OBRs were not provided. Seven days after the initiation of ibalizumab, 33/40 (83% [95% confidence interval (CI): 67-93]; P < 0.001) patients achieved the primary endpoint, a VL decrease greater than 0.5 log₁₀ copies/mL. At 25 weeks, 43% (17/40) of patients achieved a VL<50 copies/mL and the median reduction was 1.6 log₁₀ copies/mL. Subjects with CD4 ≥ 50 cells/mm³ at baseline were more likely to achieve VL < 50 copies/mL than those with CD4 < 50 cells/mm³ (24/40 [60%] vs 7/40 [18%], respectively). A mean increase in CD4 cell count was noted from baseline (150 cells/mm³ at baseline to 240 cells/mm³ at week 25). Common adverse effects included diarrhea (20%), dizziness (13%), fatigue (13%), nausea (13%), pyrexia (13%), and rash (13%). Five subjects discontinued ibalizumab with 4 due to death not considered to be related to ibalizumab. Virologic failure (defined as 2 consecutive reductions in VL from baseline of less than 0.5log₁₀ copies/ml after day 14) was documented in 7 (18%) subjects at week 25 with 3 additional subjects having viral rebound (increase in VL ≥ 1 log₁₀ copies/ml from nadir VL). Reduced susceptibility to the OBR was noted in 3 of 4 subjects in whom resistance testing was performed. Of those with virologic failure/rebound, reduced susceptibility to ibalizumab was noted in 9/10 subjects (the remaining subject had reduced susceptibility to ibalizumab unchanged from baseline). Although the study population was small, this study demonstrated that the addition of ibalizumab to OBR provided an opportunity to attain virologic suppression with minimal safety concerns in an HTE population. ¹⁶

Fostemsavir

Fostemsavir, a first-in-class HIV-1 attachment inhibitor, is an oral alternative approved for HTE-PWH with few available options due to resistance, intolerance, or safety concerns (Table 1). Fostemsavir is a prodrug converted to the active moiety, temsavir, which binds to the viral gp120 subunit preventing viral attachment to host CD4 receptors and subsequent viral entry. ¹⁷ Fostemsavir is administered twice daily as a 600 mg tablet. Coadministration of fostemsavir is contraindicated with strong CYP3A4 inducers, as temsavir concentrations may be reduced. Fostemsavir has the potential to inhibit the metabolism of concomitant agents including statins and direct-acting antivirals against hepatitis C virus.

Fostemsavir effectively and safely suppressed HIV RNA in a Phase 2b randomized, controlled trial (AI438011) in HTE subjects who were integrase strand inhibitor naïve. ¹⁸ A Phase III, placebo-controlled trial assessed the safety and efficacy of fostemsavir in HTE subjects divided into 2 cohorts (BRIGHTE study). ¹⁹ Eligibility criteria were a VL ≥ 400 copies/mL on their current regimen and an inability to use all agents in ≥4 of the available ART classes due to resistance, intolerance, contraindication, or avoidance of enfuvrtide. Cohort 1 (n = 272) consisted of patients who had ≥1 fully active, approved ART option from 1 or 2 remaining antiretroviral classes at baseline. Patients in Cohort 1 were randomized in a 3:1 ratio to receive either fostemsavir 600 mg PO twice daily or placebo plus their failing background regimen from days 1 to 8. Following day 8, patients in Cohort 1 received open-label fostemsavir plus an OBR. Cohort 2 (n = 99) consisted of patients who had no remaining active, approved ART. Subjects in Cohort 2 received open-label fostemsavir plus an OBR starting on day 9. The Cohort 1 population was 68% white, and 74% male, with a median age of 48 years, while Cohort 2 was 90% male, 74% white, and had a median age of 50 years. Cohort 1 had a baseline median VL of 4.7 log₁₀ copies/mL, a median CD4 count of 99 cells/mm³, and 88%, 29%, 74%, and 81% of patients had pan-resistance to NRTIs, INSTIs, PIs, and NNRTIs, respectively. Optimized background regimens included NRTIs (85%), INSTIs (65%), PIs (62%), and NNRTIs (33%). At baseline in cohort 1, 52% of patients had one fully active ART medication and 42% had 2 fully active ART medications. On day 8, for the primary outcome, the mean reduction from baseline in HIV-1 RNA level was −0.79 log₁₀ copies/mL in the intervention group and −0.17 log₁₀ copies/mL in the placebo group (absolute difference = −0.63 log₁₀ copies/mL [95% CI: −0.81 to −0.44] [P < 0.001]). At week 48 in Cohort 1, 146/272 (54%) of subjects achieved virologic suppression. Resistance mutations to fostemsavir were identified in 20/47 (43%) and 32/46 (70%) of subjects with virologic failure in cohorts 1 and 2, respectively. Virologic suppression was noted in 80/142 (56%) and 59/114 (52%) of Cohort 1 subjects who had 1 or 2 fully active ARVs in the OBR. Adverse effects led to discontinuation in 7% of patients and included infections, cancers, and gastrointestinal disorders. Adverse effects reported at greater than 10% included diarrhea, nausea, vomiting, headache, and cough. Fostemsavir significantly decreased viral loads in the first 8 days of therapy and led to virologic suppression with minimal toxicity in a difficult-to-treat population at 48 weeks. ¹⁹ In a 96-week follow-up, Lataillade et al, ²⁰ reported virologic suppression rates increased to 163/272 (60%) in cohort 1 and remained steady at 37/99 (37%) in cohort 2. The median CD4 count increase from baseline was 175 cells/mm³ (interquartile range [IQR]: 89-288). Virologic suppression in subjects with 0, 1, and 2 active agents in the OBR were 3/16 (19%), 92/142 (65%), and 68/114 (60%), respectively. Virologic failure increased slightly to 63/272 (23%) and 49/99 (49%) across cohorts. Susceptibility testing found substitutions of interest in 24/50 (cohort 1) and 33/44 (cohort 2) subjects for whom virologic failure and susceptibility data were available. Discontinuation due to adverse effects remained low at 3%. In contrast to the 48-week data, adverse events were reported in ≤2% of subjects. ²⁰

Similar to other studies, the BRIGHTE trial identified mutations at positions M426, S375, M475, and M434 that were associated with protocol-defined virological failure, and mutations at these sites led to a high degree of variability in IC50s. Ultimately, the correlates of virologic failure for fostemsavir have been difficult to associate with the development/presence of specific RAMs or temsavir concentrations.^9,10

Lenacapavir

Lenacapavir is a first-in-class HIV-1 capsid inhibitor approved for use in HTE-PWH with multiclass resistance, intolerance, or safety concerns (Table 1). Lenacapavir binds to capsid protein subunits important to the integrity of the capsid surrounding the HIV core. This binding disrupts multiple steps of the HIV life cycle including core transport into the nucleus, disassembly of the core and release of viral proteins in the nucleus, and postintegration capsid assembly. Lenacapavir, as part of an OBR, has 2 options for initiation of therapy followed by every 6-month maintenance dose split into 2 subcutaneous injections (Table 1). Published data describing lenacapavir PK is limited. Lenacapavir has a reported half-life of 8 to 12 weeks allowing for every 6-month administration. Injection site reactions are the most reported adverse effects and can include significant and long-lasting nodules. Lenacapavir is a substrate for CYP3A and UTGT1A1 and an inhibitor of CYP3A leading to the potential for drug-drug interactions with the use of concurrent agents using these metabolic pathways. As a long-acting injectable (LAI), the potential for drug-drug interactions may continue for 12 months or longer after the last administration of lenacapavir. In addition, if lenacapavir is discontinued, an OBR should be continued indefinitely, to minimize the risk of lenacapavir monotherapy and the development of lenacapavir resistance.

Segal-Maurer and colleagues assessed the safety and efficacy of lenacapavir in patients with MDR HIV-1 (CAPELLA study). ²¹ Eligibility criteria was a VL > 400 copies/mL, resistance to >2 ART agents from >3 of the 4 main classes, and <2 fully active ART agents from the 4 main classes. The study consisted of 2 cohorts (36 patients each): cohort 1 required stable viremia between screening and selection (defined as an HIV level >400 copies/mL with a VL decrease <0.5 log₁₀ copies/mL while on antiretroviral therapy); cohort 2 included those achieving a >0.5 log₁₀ copies/ml viral load decrease and/or a VL < 400 copies/ml while on antiretroviral therapy between screening and selection. Those excluded from cohort 1 due to sample size fulfillment were also included in cohort 2. Cohort 1 was randomized 2:1 to lenacapavir or matching placebo. In addition to their failing regimen, the lenacapavir group received oral lenacapavir 600 mg on day 1 and day 2, and 300 mg on day 8. On day 15, lenacapavir 927 mg was administered subcutaneously (continued every 26 weeks) along with OBR. The placebo group received their failing regimen plus a matched placebo on days 1 to 14 and then began OBR plus oral lenacapavir 600 mg on days 15 and 16, 300 mg on day 22, and subcutaneously every 26 weeks beginning on day 29. Cohort 2 received OBR and open-label lenacapavir (oral lenacapavir 600 mg on days 1 and 2, 300 mg on day 8, and lenacapavir 927 mg subcutaneously on day 15 and every 26 weeks thereafter). The study population was 25% female, 38% black, and a median age of 52 years. At baseline, subjects in the intervention group had lower VLs and higher CD4 counts with the median VL of 4.5 log₁₀ copies/mL and the median CD4 count of 150 cells/mm³. At baseline, 99%, 97%, 81%, 69%, and 46% of patients had resistance to >2 drugs in the following classes NRTIs, INSTIs, PIs, NNRTIs, and all 4 classes, respectively. Optimized background regimens included NRTIs (85%), INSTIs (65%), PIs (62%), and NNRTIs (33%). On day 15, 88% and 17% of patients in the treatment and placebo groups, respectively, achieved the primary outcome of a VL decrease ≥0.5 log₁₀ copies/mL (absolute difference of 71% [95% CI: 35-90; P < 0.001]). At 26 weeks in the combined cohorts, 59/72 (82%) of patients achieved a VL < 50 copies/mL, and 63/72 (88%) achieved a VL < 200 copies/mL. Eight patients developed resistance to lenacapavir: 6 had an M66I mutation, 1 had a Q67H + K70R, and 1 had a K70R. Resuppression occurred in 4 of the 8 participants. Poor adherence and no active drugs in the OBR were reported in 50% of subjects with resistance. No discontinuations occurred due to toxicity. Common adverse effects included injection reactions (63%), pain (31%), swelling (31%), erythema (25%), and nodule formation (24%). ²¹ In the 52-week follow-up of combined cohorts, 56/72 (78%) and 59/72 (82%) had VL < 50 copies/mL and <200 copies/mL, respectively with one participant with poor adherence developing resistance (Q67H mutation). ²² Adverse effects were similar at 26- and 52-weeks. Almost two-thirds of subjects reported mild-moderate injection site reactions with one subject discontinuing therapy due to nodules. While the injection site reactions in general were short-lived (median 6 days), nodules and indurations persisted for a median of 227 and 113 days postadministration, respectively. These studies suggest lenacapavir is safe and effective for reducing VL in HTE patients; however, resistance development must be considered.^21,22

Discussion

Antiretroviral agents with novel mechanisms of action have made achieving and sustaining virologic suppression a reality in most of the HTE-PWH. The availability of second-generation INSTIs, ibalizumab, and fostemsavir as components of the OBR likely contributed to the steady increase in virologic suppression rates from <50% in the original ibalizumab trials to >80% in the LEN trials, highlighting the critical importance of active agents in the OBR (Table 2). General recommendations are provided for the management of HTE individuals. ² An emphasis on the need for ≥2 active agents in OBR to achieve virologic suppression is supported by the ibalizumab, fostemsavir, and lenacapavir clinical trials.^16,19,21 Drug intolerance, interactions, and resistance complicate ARV selection. If an OBR with ≥2 agents from the 4 major classes cannot be realized due to these considerations, the addition of an agent or agents with a novel mechanism should be considered. ²

Table 2.

Summary of Clinical Trials for Ibalizumab, Fostemsavir, and Lenacapavir in Heavily-Treatment Experienced People Living With HIV.

Study	Ibalizumab 15	Fostemsavir19,20	Lenacapavir21,22
Inclusion criteria related to baseline resistance and viral load	Study Inclusion • Baseline resistance to a least 1 drug in 3 classes • VL > 1000 copies/ml on ART	Study Inclusion • Baseline “exhaustion” of all agents in 4/6 ART classes a • VL > 400 copies/ml on ART Cohort Inclusion Cohort 1: 1 or 2 fully active, FDA-approved agents in OBR Cohort 2: no fully active, FDA-approved agents in OBR	Study Inclusion • Baseline resistance to ≥2 agents from 3 of 4 main classes b , and • ≤2 agents available with full activity from 4 main classes b (fostemsavir and ibalizumab available for use) Cohort Inclusion Cohort 1: stable viremia ≥ 400 copies/ml between screening and cohort selection while on ART Cohort 2: reduced viremia between screening and cohort selection and/or VL <400 copies/ml while on ART, or Cohort 1 overflow (ie, met Cohort 1 criteria, but Cohort 1 selection complete)
Number of active agents in optimized background regimen (OBR)	≥1 active drug (could be investigational c )	Cohort 1: 1 or 2 fully active, FDA-approved agents d in OBR Cohort 2: 0 fully active, FDA-approved agents e in OBR	Cohort 1: 0-≥2 active agents in OBR Cohort 2: 0-≥2 active agents in OBR (could include agents not in 4 main classes, ex. ibalizumab, fostemsavir, maraviroc, enfuvrtide)
Virologic suppression f (n [%])	17/40 (43%) wk 25	Cohort 1: 146/272 (54%) wk 48 163/272 (60%) wk 96 Cohort 2: 38/99 (38%) wk 48 37/99 (43%) wk 96	Cohort 1: 29/36 (81%) wk 26 30/36 (83%) wk 52 Cohort 2: 30/36 (83%) wk 26 26/36 (72%) wk 52
Virologic suppression f (n [%]) based on number of active drugs in OBR 0 active ART OBR 1 active ART OBR 2 active ART OBR	Not eligible NR NR	NR 80/142 (56%) wk 48 92/142 (65%) wk 96 59/114 (52%) wk 48 68/114 (60%) wk 96	9/12 (75%) wk 26 9/12 (75%) wk 52 24/27 (89%) wk 26 20/26 (77%) wk 52 26/33 (79%) wk 26 27/34 (79%) wk 52
VL <200 cp/ml (n [%])	20/40 (50%) wk 25	NR	Cohort 1: 32/36 (89%) wk 26 31/36 (86% wk 52 Cohort 2: 31/36 (86%) wk 26 28/36 (78%) wk 52
Virologic failure	7/40 (18%) g 3/40 (8%) virologic rebound	Cohort 1: 49/272 (18%) h Cohort 2: 46/99 (46%)	Cohort 1:11/36 (31%) i Cohort 2:8/36 (22%)

Abbreviations: ART, antiretroviral therapy; NR, not reported; OBR, optimized background regimen; VL, viral load; wk, week.

^a“exhaustion” defined as resistance, intolerance, or contraindication to all agents in the integrase strand transfer inhibitor (INSTI), nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), CCR5 antagonist CLA, or entry inhibitor classes, or refusal to administer enfuvrtide.

^bNRTI, NNRTI, INSTI, and PI.

^c17/40 required fostemsavir to meet ≥1 active drug.

^d84% used DTG.

^e15 patients received ibalizumab (which was investigational at the time).

^fdefined as VL < 40 or 50 copies/ml depending on clinical trial definition.

^gVirologic failure defined as 2 consecutive measurements after day 14 that showed a reduction from baseline in viral load of less than 0.5 log₁₀ copies per milliliter.

^hVirologic failure was defined as: <week 24, an HIV-1 RNA ≥400 copies/ml after previous confirmed HIV-1 RNA <400 copies/ml or an increase of at least 1.0 log₁₀ in the HIV-1 RNA level above the nadir (i.e., ≥40 copies/ml); ≥week 24, an HIV-1 RNA level ≥ 400 copies/ml.

ⁱVirologic failure for the purpose of resistance analysis was defined as any of the following: a confirmed HIV-1 RNA ≥ 50 copies/ml and a decrease of less than 1 log₁₀ copies/ml at week 4 after the initiation of oral lenacapavir, a confirmed rebound in HIV-1 RNA to ≥50 copies/ml after previous measure of <50 copies/ml, a confirmed increase from the nadir value of >1 log₁₀ copies/ml, or an HIV-1 RNA of ≥50 copies/ml at week 26 or at the time of trial discontinuation.

Several points should be emphasized when considering ibalizumab, fostemsavir, and lenacapavir. Routes and frequencies of administration vary (Table 1). Individuals wanting to minimize additional pills or are averse to injections or needles have new options. If discontinuing an LAI ARV like lenacapavir, an OBR should be continued indefinitely to prevent functional monotherapy and potential lenacapavir resistance. If ibalizumab or lenacapavir doses are missed, administration of loading doses may be required. All 3 agents are well-tolerated in clinical trials. Injection site reactions, including potentially persistent nodules, have been reported with lenacapavir. Drug interactions are a consideration with fostemsavir and lenacapavir, so concurrent medications should be reviewed before initiation. No renal adjustments are needed with any of the 3 agents. Ibalizumab, fostemsavir, or lenacapavir use should be avoided in pregnancy (lack of published data). The long half-life of lenacapavir should be considered if used in women of childbearing potential.

Finally, obtaining novel antiretrovirals can be arduous. An assessment to determine access to the preferred agent should be completed before any alterations in OBR to minimize the risk of interruption of therapy. All 3 agents have patient assistance programs but medication availability via government-based, private and commercial insurance, and state drug assistance programs varies. Fostemsavir is available via community pharmacies. Ibalizumab and lenacapavir require administration in a clinic or infusion center. Ibalizumab will require consistent intravenous access and both agents will require coverage of not only drug acquisition but also administration costs.

Conclusion

With the approval of ibalizumab, fostemsavir, and lenacapavir, virologic suppression is now an achievable goal for most HTE-PWH. While these medications are safe and effective, using an OBR (which may include ibalizumab, fostemsavir, and/or lenacapavir) is still paramount to attaining virologic suppression and minimizing the risk of resistance development. Significant differences among the 3 agents do exist and include routes of administration, dosing frequency, adverse effects, and potential for drug-drug interactions. These characteristics should be considered and discussed with patients when deciding among these antiretroviral agents.